Researchers are re-engineering the lethal design of bacteria and viruses to find ways to stop their infectious cycles. Vaccines show the immune system important parts of the virus so that the immune system can prepare the tools to fight the real virus effectively—vaccines trick the immune system into responding like it has previously seen the virus. But the immune system also makes killer cells, which stop viral replication by killing any infected host cells.
There are many potential vaccine candidates in the pipeline globally, made using a wide range of new technologies. These vaccine technologies include the use of subunit vaccines: researchers make viral proteins and put them into the body, so that the immune system makes antibodies against those viral proteins. Other technologies trick the body to make those viral proteins itself, these include delivery of RNA in liposomes or DNA plasmids in nanoparticles, as well as modified safe viruses and existing vaccines.
By studying virus life cycles and how viruses are detected by the immune system, we can discover new ways to target the virus and treat viral disease even without a vaccine. Severe cases of viral pneumonia often end up with an associated bacterial infection. So, despite COVID being caused by a virus, antibiotics are really important to treat the associated bacterial infections. As antibiotic-resistant bacteria are an increasing global problem, researchers at IMB are investigating the surface activity of bacteria at molecular level and have discovered how they elude the human immune system.
They are also looking at developing new therapies to treat resistant bacteria, and working to help r esearchers around the world discover new antibiotics. Skip to menu Skip to content Skip to footer.
Site search Search. Site search Search Menu. In our oceans, there are 10 billion times more bacteria than there are stars in the universe. The millions of viruses in the world laid end to end would stretch for million light years.
Bacteria are free-living cells that can live inside or outside a body. During exponential growth, A. However, during stationary phase, the number of chromosomes in an individual cell can increase to This unique plasticity in genome copy number is not well understood, and continued research is required to better understand the advantage of accumulating many chromosomes in these cells during stationary phase. These bacteria are intracellular symbionts of certain aphid species.
This mutualistic relationship between aphid and bacterium evolved millions of years ago. Although closely related to E. In one Buchnera species, the genome is composed of one kilobase Kb chromosome and two plasmids, which encode the biosynthetic pathways for several amino acids. It has been shown that the number of genome copies in Buchnera cells is related to the developmental stage of their host aphid; as an aphid enters into adulthood, the genomic copy number in individual Buchnera cells increases.
As the aphid host ages, the genomic copy number in Buchnera decreases. It has been proposed that this fluctuation in copy number may be due to the bacterium purging itself of genomes with deleterious mutations, ensuring only viable chromosomes are transmitted to the next generation of aphids. These ubiquitous, gram-negative, motile, rod-shaped soil bacteria are the causative agent of crown-gall disease in plants.
Agrobacterium tumefaciens is referred to as a natural genetic engineer, as it is capable of transferring DNA from itself into plant cells. And beyond that, there are also other possible explanations besides the cytoskeletal hypothesis for why eukaryotes and bacteria are different; this is a fourth level, even more general and more speculative, but one that I think helps tie this whole story together.
The first thing to think about is the question of protein self-assembly, because classically, when we think about the cytoskeleton, we imagine lots of little subunits that are able to assemble in an oriented fashion, to make larger structures. The ability of proteins to form homo-oligomers is very prevalent and, in fact, I would say it is almost the default thing for proteins to be able to do.
Structural biologists have done a very nice job of breaking down the kinds of symmetries you can get in these homo-oligomers into different kinds of classifications. Really making a helix is just one particular phylogenetic group, if you will, of the kinds of structures that proteins can make by self-assembly.
Now there are two really nice things about helices. One is that a helix enables you to make structures of variable length, while most other oligomer types make a closed structure with a defined size, such as a viral capsid. But a helix that grows by addition of subunits onto the end can in principle be tuned over a very wide size or length range.
They used protein structural arguments to explain that when you allow many copies of the same protein to aggregate together you can hardly help but make a helix Figure 3 a. If you allow a protein to self-assemble, a helix of some kind is going to be the default. Helical protein filaments formed by self-assembly. For any globular protein of arbitrary shape, as shown at the top, considered as interacting with a second copy of itself in all possible orientations, there will be some pair of surface patches that result in optimal binding energy.
It is highly unlikely that those two interface patches will happen to reflect any specific geometrical symmetry. When many copies of the same subunit self-associate by binding to one another through these surface interactions, a one-start helix with a single protofilament is the default structure formed, as shown in the middle.
At bottom, if weaker interactions can also form laterally between subunits, multi-start helices may be stabilized adapted with permission from the Royal Society of Chemistry [ 62 ]. Yes, hemoglobin is a terrific example. In sickle-cell disease, a single point mutation in hemoglobin changes one charged residue on the surface to a neutral residue [ 64 ], and now in this dense cellular bag of the erythrocyte, filled almost entirely with one protein, you have a condition where the oxygen-depleted form of hemoglobin is able to self-assemble into a spectacularly beautiful helical structure with 14 protofilaments that looks absolutely classically like a microtubule or some other cytoskeletal filament [ 63 ] Figure 3 b.
Sickle-cell hemoglobin is, of course, a very famous example of many principles of protein structure and function, but in this particular case it clearly shows that when you take a very soluble protein and create a condition in which it is not quite soluble, a helix is what you get.
If any old protein will assemble into a helix, then what is special about the cytoskeletal proteins? There are several possible answers, but one that I find compelling is that the common feature of the universally conserved cytoskeletal proteins - the actin superfamily, the tubulin superfamily - is that both of them are nucleotide hydrolases.
They use the energy of nucleotide hydrolysis to switch between at least two distinct conformations. One of those conformations has a lower energy barrier to forming a filament than the other one. What this means is that if you can couple nucleotide hydrolysis kinetics to the interactions that the protein can form when it is in a helix, you can use the energy of nucleotide hydrolysis to regulate stability [ 65 ].
You can have the filaments assemble when the subunits have the ATP or GTP bound, and then after hydrolysis takes place, the energy released by hydrolysis is stored in the lattice in such a way that now disassembly becomes favorable. And this means that within a cytoplasm, where you have a good supply of ATP and GTP, you could have constantly dynamic filaments without having to change the concentration of anything.
Absolutely not. And in fact bacteria use the cycle of nucleotide hydrolysis to modulate the assembly of their cytoskeletal filaments quite nicely. This is not the difference between bacteria and eukaryotes. If you look at the dynamics of, for example, FtsZ, it turns over very fast, even in the cytokinetic ring. You can see a beautiful ring that persists stably for some minutes before cytokinesis and before the cells separate [ 66 ], and yet there are very convincing photobleaching studies showing that the filaments within that ring are continuously turning over just like the microtubules in a mitotic spindle, or the actin filaments in a lamellipodium.
Indeed it has been shown that mutants in FtsZ that have slowed GTP hydrolysis kinetics also have a slower turnover rate inside the living cell [ 67 ]. ParM, which is the very well characterized actin homolog that is used to segregate plasmids in bacteria [ 31 ], even shows dynamic instability [ 54 ], which is one of the classic outcomes of the coupling of assembly to nucleotide hydrolysis for eukaryotic cytoskeletal filaments [ 65 , 68 — 70 ].
I think it is very clear that those intrinsic, dynamic properties of the self-assembling filaments - the coupling to nucleotide hydrolysis, the rapid turnover, kinetic properties like dynamic instability - those things are universal in cellular cytoskeletons Figure 4. That is not a problem for bacteria, and that is not the difference between bacteria and eukaryotes. Dynamic instability of cytoskeletal filaments from eukaryotes and bacteria.
Left: direct observation using dark-field microscopy of a microtubule undergoing dynamic instability. Middle: graph showing position of plus ends top and minus ends bottom for two dynamically unstable microtubules, with repeated cycles of growth and shrinkage.
Numbered points correspond to individual video frames as labeled on the left reprinted by permission from Macmillan Publishers Ltd: Nature — , copyright [ 69 ]. Right, schematic diagram showing the connection between nucleotide hydrolysis and dynamic instability Copyright from Molecular Biology of the Cell, 5th edition by Alberts et al.
Left: fluorescence time-lapse images of a single ParM filament over time. Blue arrowhead shows position of initial filament appearance; red arrowheads mark the most extreme positions of the two tips. Right, traces of filament length over time for six different ParM filaments, showing a phase of growth followed by catastrophic shrinking.
Science , — Reprinted with permission from AAAS [ 54 ]. Moving on to the second perspective for my argument, if helical protein self-assembly regulated by nucleotide hydrolysis is universal, then what can we say about the role of regulated nucleation of cytoskeletal filaments in determining the difference between bacterial and eukaryotic cell organizational strategies?
Here I think we are digging into much richer soil. As a cell, you would really have to put a lot of effort into not nucleating them. For ParM, the filaments undergo very rapid dynamic instability and shrink back to nothingness unless they are stabilized by encountering cognate segments of DNA bound by the correct protein partner, both of which are normally found on the plasmid that is using ParM for segregation [ 71 ].
This mechanism rather neatly ensures that ParM filaments forming in a cell will be stabilized to push the plasmids apart only when there are two copies of the plasmid present, one to stabilize each end of the normally unstable filament. For FtsZ, its major regulator is a destabilizing factor, MinC [ 72 ], which undergoes its own very fascinating form of spatial regulation, but the short version is that the FtsZ ring that initiates bacterial cell division can form only where MinC is not; that is, FtsZ nucleation is spontaneous, but filament stability is regulated.
MinD self-assembles on the bacterial membrane, and the MinD filaments are then destabilized by another protein factor, MinE. The kinetic interaction between MinD assembly and MinE destabilization results in spectacular oscillatory positioning of the MinC inhibitor inside of cells [ 74 ] and self-propagating waves when reconstituted in vitro [ 75 ].
In brief, this impressively dynamic and very precise system that the bacterial cell uses to choose the site of division depends on the spontaneous nucleation of one filamentous structure MinD that is destabilized by a regulator MinE. The biological purpose of MinD and MinE is to regulate the localization of MinC, which acts to destabilize the spontaneously nucleating tubulin homolog FtsZ.
Over and over for bacterial cytoskeletal and cytoskeletal-like elements, we are seeing spontaneous nucleation followed by spatially localized stabilization or destabilization as the general organizing principle.
Again the really surprising thing here is that, for the cases that we understand well, nucleation plays no obvious part in the spatial regulation of cytoskeletal assembly for bacteria; everything where we understand the molecular details of spatial regulation regards filament stabilization and destabilization. My examples here are the best-characterized systems that we know in bacteria.
For most of the other examples of bacterial cytoskeletal filaments, too little is known about their dynamics to enable us to guess how the nucleation versus stabilization equation will play out. I think it will be very, very interesting in the next few years to see if this is really a universal, decisive difference between the eukaryotes and the bacteria, or just an intriguing feature of the first few well understood systems.
Honestly, I really think bacteria could do that if they wanted to. But so far we do not know of any bacterial proteins that are specifically dedicated to nucleation of bacterial cytoskeletal filaments. There are many cases where having localized nucleators has been shown to be sufficient to give you really very interesting kinds of self-organized systems.
A famous example I really like comes from experiments on dropping centrosomes or beads covered with microtubule nucleators into little microfabricated wells - you can grow up asters of microtubules and these will push the bead or the centrosome into the center of that well [ 76 ] Figure 5 a.
Each growing microtubule end pushes against the wall of the well, generating a few picoNewtons of force [ 77 ], and the forces are equally balanced when the nucleating bead is near the middle. Because the microtubules are dynamic, and specifically because they are undergoing dynamic instability and occasionally shrinking back to their origin, the system does not get stuck and the centering can be maintained.
This mechanism of self-centering by having centrally nucleated microtubules nudging at walls appears to be the way that the fission yeast Schizosaccharomyces pombe maintains the mid-cell location of its nucleus [ 78 ].
In the example of the nucleating bead in the well, we can see that just by localizing nucleation, you can set up a coordinate system that will tell you within the microchamber or within the cell where you are and which direction is inside and which is outside.
If you imagine some cargo attached to a molecular motor encountering this assembly at any point in the space, the cargo attached to a minus-end directed motor such as dynein will end up in the middle, and the cargo attached to a plus-end directed motor such as kinesin-1 will go to the periphery.
Self-centering activity of dynamic microtubule arrays. Left: diagram of crosslinked motors reorienting microtubules. Right: fluorescence image of an aster formed in a microwell by this mechanism reprinted by permission from Macmillan Publishers Ltd: Nature — , copyright [ 79 ]. Now this brings me to the exception I mentioned earlier where bacterial cytoskeletal proteins can actually form a type B structure, specifically a self-centering aster.
This has been seen for at least two of the eukaryotic cytoskeletal homologs associated with independent DNA elements in bacteria, an actin homolog that is encoded by a plasmid [ 80 ] and a tubulin homolog that is encoded by a bacteriophage [ 81 ]. In both cases, it appears that the self-centering activity of the associated cytoskeletal filament structures is useful to promote replication or segregation of the associated DNA element.
In these cases, the plasmid or bacteriophage DNA itself is acting as the nucleating center. Other filament-forming proteins encoded by plasmids in bacteria, such as ParA, appear to help regulate the positioning of their plasmids in much the same way, even though these are not obviously homologous to one of the eukaryotic cytoskeletal proteins [ 82 ]. So it is clear that the basic mechanics for self-centering by localizing nucleation of self-assembled filaments do work just fine with the bacterial cytoskeletal and cytoskeletal-like proteins.
But, and I think this is an important distinction, these structures are self-centered in more than just one way; the oriented cytoskeletal filaments do not appear to serve as tracks to provide spatial information for other cellular elements.
Unlike the microtubule asters that set up a global coordinate system used by molecular motors and membrane-enclosed organelles to generate large-scale organization in eukaryotes, the plasmid and bacteriophage systems seem to operate with every man for himself.
That is, they spatially localize only the very DNA element that encodes them. This observation points out a really interesting and probably important difference between bacteria and eukaryotes that I think is fundamental.
When people first started discovering all of these tubulin and actin homologs in bacteria, many of us were initially amazed at how many there seem to be, with each one apparently tuned for a single specific purpose. But maybe what we should really be amazed about is how few tubulins and actins seem to be present in eukaryotic cells.
For the major filament-forming cytoskeletal subunits in eukaryotes, there may be multiple genes encoding them in any given organism, but the subunits are typically able to assemble together into a single all-purpose cytoskeleton that is used for an outrageous variety of biological processes.
In eukaryotes, functional variety appears to be largely carried by the large numbers of different kinds of actin-binding and tubulin-binding proteins that are present [ 83 , 84 ].
Frankly it is rather extraordinary that the same kind of microtubule structure can be used to make mitotic spindles and beating cilia. As far as I can tell, this kind of creative multi-purposing of cytoskeletal filaments just does not happen in bacteria, where the rule seems to be one filament for one function. This is the second major group of cytoskeletal regulators, after the nucleating proteins, that I suspect might simply be missing in bacteria.
Like regulated nucleators, cytoskeletal motor proteins can cooperate with their filaments to generate very large-scale structures. For example, clusters of motor proteins can generate very nice organized asters in vitro , much as the nucleating beads do, even if their associated filaments are stabilized and non-dynamic [ 79 ] Figure 5 b.
The motors, because they move toward only one end of the polarized filament substrate, are essentially able to sort out a disorganized clump of mixed-polarity filaments into something nice and orderly with uniform polarity.
So the cytoskeletal molecular motors, together with localized nucleators, can make the type B cytoskeletal structures that I am arguing are so important for eukaryotic cell organization. Obviously bacteria do have some kinds of molecular motors, if we define molecular motors very generally as just being engines that convert chemical energy into mechanical energy, which I think is a fair definition. And the bacterial flagellar motor is just spectacular.
It is an extraordinarily energy-efficient and complicated and beautiful object [ 85 ]. In fact, it is so beautiful that in the United States, the anti-evolutionary creationists seized upon it as being something so fantastic that it could not possibly have evolved [ 86 ]. Happily there is actually very nice structural evidence that evolution of the flagellar rotor has indeed occurred [ 87 ]. Alex Weiss Aparicio. Scientific Scribbles The difference between bacteria and viruses.
Bacteria A prokaryotic cell like a bacterium does not have a cell nucleus, the DNA just floats around in the cell. Viruses Viruses are just genetic material DNA in a protein shell. Viruses attack a bacterium, Image credit: Wikimedia commons The virus DNA manipulates the cell and turns it into a virus replication machine. The enemy of my enemy is my friend As you now know a virus needs to kill its host cell to reproduce so they are all bad for us?
October 22, Categories Class of Posted by Alex Weiss Aparicio. Previous Previous post: How to let dinosaur come back?
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